The overall objective of this project is to generate new, potent, selective antimalarials that act through a novel mechanism of blocking the plasmodial surface anion channel (PSAC), a previously unexploited and highly conserved plasmodial target. Human malaria is caused by five species of protozoan parasites in the genus Plasmodium. It is estimated that there are more than 500 million clinical cases of P. falciparum malaria and one million deaths annually, with ninety percent of the deaths occurring in sub-Saharan Africa. By far the most dangerous of these is P. falciparum, which accounts for nearly all malaria deaths. The malaria parasites, most importantly P. falciparum, require two hosts, which are humans and female Anopheles mosquitoes. Disease is transmitted to humans from the bite of an infected mosquito. There are no effective vaccines available to prevent malaria, but several small molecule treatment options exist, such as chloroquine (CQ) and artemisinin. CQ, once the mainstay of malaria treatment, has lost much of its efficacy because of mutations that confer resistance. New small molecule drugs, especially those working on new targets that may be less susceptible to acquired resistance, are desperately needed. PSAC is a newly discovered essential antimalarial target which was recently validated by gene identification experiments. The channel is produced by the parasite and inserts into the infected erythrocyte membrane. It was recently demonstrated that PSAC inhibitors, discovered by high-throughput screening, kills parasites by direct action on this channel. In preliminary studies, Dr. Sanjay Desai, NIH, developed and applied a screen for PSAC inhibitors using a sorbitol transport assay, that resulted in the identification of several chemotypes that displayed inhibitory potencies (K0.5 PSAC block) in the nanomolar range. Compounds also inhibited plasmodial growth with low micromolar to low nanomolar potencies (IC50). Two of the hit compound chemical scaffolds were chosen for medicinal chemistry optimization on the basis of their potency, low cytotoxicity, tractability of synthesis and overall favorable in vitro drug-like ADM results. The first, E912-0081 (MBX 2366) was designated as the primary scaffold, upon which chemistry SAR efforts will be focused. The second, C791-0105, has been selected as a backup scaffold should the primary scaffold fail to achieve the milestones set forth in Aims 1-3. The Phase I project will focus on optimizing in vitro properties such as potency, solubility and variou pharmacokinetic parameters predictive of in vivo efficacy and leading to identification of a lead compound(s). The best lead compound antimalarial PSAC inhibitors will then progress to Phase II for in vivo pharmacokinetics, toxicology and efficacy studies. The interdisciplinary approach, which will merge the antimalarial expertise of Dr. Desai with the anti-infective research and development capabilities of Microbiotix, will produce inhibitors for a newly discovered, essential and conserved malarial target and provide new treatment options for resistant infections.